A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

Article abstract of DOI:10.3762/bjoc.14.196

Chloramines are an important class of reagents, providing a convenient source of chlorine or electrophilic nitrogen. However, the instability of these compounds is a problem which makes their isolation and handling difficult. To overcome these hazards, a continuous-flow approach is reported which generates and immediately reacts N-chloramines directly, avoiding purification and isolation steps. 2-Chloramines were produced from the reaction of styrenes with N-alkyl-N-sulfonyl-N-chloramines, whilst N-alkyl or N,N’-dialkyl-N-chloramines reacted with anisaldehyde in the presence of t-BuO₂H oxidant to afford amides. Primary and secondary imines were produced under continuous conditions from the reaction of N-chloramines with base, with one example subsequently reduced under asymmetric conditions to produce a chiral amine in 94% ee.

Full text of DOI:10.3762/bjoc.14.196

A general and atom-efficient continuous-flow approach
to prepare amines, amides and imines via
reactive N-chloramines
Katherine E. Jolley1, Michael R. Chapman1 and A. John Blacker*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2220–2228.
1School of Chemistry, Institute of Process Research and
Development, University of Leeds, Leeds, LS2 9JT, United Kingdom
and 2School of Chemical and Process Engineering, University of
Leeds, Leeds, LS2 9JT, United Kingdom
doi:10.3762/bjoc.14.196
Received: 16 April 2018
Accepted: 10 August 2018
Published: 24 August 2018
Email:
A. John Blacker* - j.blacker@leeds.ac.uk
This article is part of the Thematic Series "Integrated multistep flow
synthesis".
* Corresponding author
Guest Editor: V. Hessel
Keywords:
continuous flow; CSTR; N-chloramine; synthetic methods; telescoping
© 2018 Jolley et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Chloramines are an important class of reagents, providing a convenient source of chlorine or electrophilic nitrogen. However, the
instability of these compounds is a problem which makes their isolation and handling difficult. To overcome these hazards, a con-
tinuous-flow approach is reported which generates and immediately reacts N-chloramines directly, avoiding purification and isola-
tion steps. 2-Chloramines were produced from the reaction of styrenes with N-alkyl-N-sulfonyl-N-chloramines, whilst N-alkyl or
N,N’-dialkyl-N-chloramines reacted with anisaldehyde in the presence of t-BuO2H oxidant to afford amides. Primary and second-
ary imines were produced under continuous conditions from the reaction of N-chloramines with base, with one example subse-
quently reduced under asymmetric conditions to produce a chiral amine in 94% ee.
Introduction
N-Chloramines are versatile reagents, however, their availabili- limited by the availability of suitable equipment. Microreactors
ty is restricted by their stability, so useful would be in situ have been used for mixing biphases and employ either static
methods to produce and use them [1,2]. The continuous-flow mixers or shaped chambers and channels that repeatedly split
methodology is useful in this context, enabling control over and mix the liquids [3-5]. These rely on flow rates within the
reaction exotherms and improved measures for containment. To mixing zone that are sufficient to overcome phase separation
evaluate the use of N-chloramines in the laboratory requires [6]. Actively mixed, multistage and variable residence time
multiphase flow methods, and until recently these have been (tres) continuous stirred tank reactors (CSTRs) allow much
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Beilstein J. Org. Chem. 2018, 14, 2220–2228.
lower flow rates and therefore longer tres for slow reactions affects its partition between phases. Herein, we report improve-
[7,8]. The use of CSTRs to carry out sequential or multistep ments to this process and the use of N-alkyl-N-chloramine in
reactions has been exploited by Ley and others [9-11]. The subsequent continuous-flow reactions (Figure 1).
strategy is useful, since it has the potential to eliminate time-
consuming and costly product isolations. In these systems, These reagents can be used as electrophilic or radical amination
the reactants and products are fluids which are contacted agents in a wide range of reactions [14]. In the present study,
with solid-supported reagents that after some time require we opted to evaluate the addition of N-alkyl-N-chloramines
regeneration, which is not convenient within chemical manufac- with (a) alkenes to produce amines, (b) aldehydes to give
ture.
amides, (c) reaction with a base to afford imines. Several
alkenes are known to react with N-haloamines to form
Chloramine itself is unstable, though has been produced safely aziridines and other N-heterocycles. Typically, the reactions
at large scale using continuous-flow methods; in fact, chlor- require a catalyst (e.g., Cu, I2) [17,18,27], whilst more active
amine has been used as an intermediate in the manufacture of reagents such as chloramine-T with osmate catalysts have been
hydrazine using the Raschig process [12,13]. N-Alkyl-N-chlor- used to make 1,2-aminoalcohols and diamines [28-33]. Im-
amines are equally unstable, yet have only been prepared in proved methods for the formation of amides remain an impor-
batch via reaction of a primary or secondary amine with tant goal for the pharma industry. In this regard, the reaction of
Cl2 gas, N-chlorosuccinimide, chloramine-T or hypochlorite N-chloramine with aldehydes, t-BuO2H and iron or copper cata-
salts [14,15]. Whilst Cl2 gas is atom efficient it is difficult to lysts to give secondary and tertiary amides was reported in
handle, with associated toxicity, and the acid byproduct which batch recently [33,34], though safety concerns upon scale-up
leads to N-chloramine hydrolysis [16]. On the other hand, makes this a useful reaction to translate to flow. Likewise,
N-chlorosuccinimide or chloramine-T are commonly employed, imines are an important class of compounds and are increas-
being commercially available, stable and straightforward to ingly used as precursors to optically active amines [35-39].
handle, though both exhibit poor atom economy [17-21]. Sodi- Whilst normally prepared via a corresponding carbonyl com-
um hypochlorite (NaOCl) solutions are less widely used, yet pound, final dehydration can be problematic. The oxidation of a
readily available, economic and provide an atom efficient racemic amine and subsequent chiral reduction may offer a
reagent for N-chloramine formation [22-24].
valuable alternative if coupled into a sequential flow protocol.
There are reports on the formation of imines from N-chlor-
A continuous-flow process for the oxidation of alcohols using amines using bases (e.g., NaOMe, KOt-Bu, NEt3 and NaOH)
NaOCl as a phase-transfer catalyst was recently reported [25]. [40-45], with one specific study using this technique to
We have published a communication that describes the continu- racemise and resolve enantiopure tetrahydroquinolines [46,47],
ous mixing of aqueous NaOCl and an organic solution of sec- and another accessing an intermediate to the drug telaprevir
ondary amine, using either a tubular reactor with in-line static [45]. Our study complements these findings, by supplying a
mixers or a single stage CSTR [26]. The reactor was selected to continuous-flow oxidation–reduction sequence which tele-
provide a tres for optimal conversion. This was achieved accord- scopes both N-chloramine and imine intermediates to produce
ing to reaction kinetics and hydrophobicity of the amine, which chiral amines.
Figure 1: Continuous-flow process to produce and react N-chloramines.
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Beilstein J. Org. Chem. 2018, 14, 2220–2228.
Results and Discussion
developed by our group recently [8], which enables efficient
N-Chloramine formation
mixing over long tres (Figure 2).
N-(Di)alkyl-N-chloramines have been prepared in continuous
organic–aqueous biphasic flow using either static mixers or a Using a 5-stage variant, various unsymmetrical N-chloramines
single-stage CSTR [26]. The choice of reactor and definition of were produced with unprecedented productivities (Table 1).
tres for this reaction is governed by both the thermodynamic
phase partition parameter of reactants and mixing efficiency The rapid nature of this chlorination step makes in situ genera-
which control mass transfer between each phase (and thus, reac- tion and consumption feasible in flow mode. Comparing
tion rate). We decided to exploit a multi-stage cascade CSTR Table 1, entries 1 and 3, the 5-stage CSTR, with one fifth the
Figure 2: Left: Laboratory scale CSTR developed by our group [8]. Right: 5-stage CSTR configuration using co-feeds of amine in toluene and
aqueous NaOCl.
Table 1: Continuous N-chloramine formation.
entry starting material
product
reactora (vol/mL)
tres (min)
conversion (%)b
productivity (mol L−1 h−1)
1
2
3
4
5
6
1
1
1
2
3
4
5
5
5
6
7
8
SM (6)
20
25
5
89
1.3
1.2
5.6
2.8
0.9
3.0
CSTRc (50)
CSTRd (10)
CSTRd (10)
CSTRd (10)
CSTRd (10)
100
94
10
30
10
92
93
100
aSM = static mixer. bDetermined by 1H NMR spectroscopy. c1-Stage CSTR. d5-Stage CSTR.
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volume of that in Table 1, entry 2, provides a much shorter 160–200 °C. This profile peaks at 188 °C, corresponding to an
tres than the in-line static mixer (SM) with comparable conver- enthalpy of decomposition of −84.7 kJ mol−1 (see Supporting
sion of N-benzyl-N-methylamine (1) to the N-alkyl-N-chlor- Information File 1, S2). A maximum safe operating tempera-
amine 5 at steady state, representing a productivity value of ture of 110 °C was implemented to avoid thermal decomposi-
5.6 mol L−1 h−1. The same reactor geometry was used to chlori- tion and thermal runaway.
nate primary, secondary acyclic and cyclic amines 2–4 in
conversions between 92–100%, with productivities ranging be- The direct reaction of N-chloramine 11, or the benzyl-substi-
tween 0.9–3 mol L−1 h−1 (Table 1, entries 4–6). In each case, tuted variant 12, led to a single regioisomer of the amine prod-
separation of the product-rich toluene phase avoided N-chlor- uct in a lower reaction time than the analogous reaction using
amine isolation and allowed direct deployment in further reac- 16 (15 minutes vs 24 hours in batch mode; Supporting Informa-
tions.
tion File 1, Table S1, entry 2 and Table 2, entries 1–5. The
products 14 and 15, prepared in batch, were isolated in 78 and
68% yield, respectively, and characterized (see Supporting
Reaction of N-chloramine with alkene
Initially our study tested the reaction of N-chloromorpholine Information File 1, S4). These standards enabled monitoring of
(16) to styrene (13) varying Cu catalyst loading and a range of the steady-state conversion in continuous flow by 1H NMR.
temperatures. The anti-Markovnikov addition product was ob-
served with 10% CuI catalyst loading, at ambient temperature. Following an optimization study, it was found that the Cu cata-
However, it required 24 hours (see Supporting Information lyst could be omitted when operating at 100 °C for 1 hour reac-
File 1, S1), and this slow reaction prevents sensible translation tion time in batch, providing quantitative conversion to product
of the process into continuous flow. Despite trying alternative (Table 2, entry 4). Conducting the same reaction under an atmo-
catalysts or other conditions no improvement was found. sphere of air or in the presence of TEMPO, suppressed all prod-
Instead, the more electron-poor N-chloro-N-methyl-p-toluene- uct formation (Table 2, entry 5). Due to the safety concerns of
sulfonamide (11) was investigated as substrate. Differential scaling-up such a batch reaction, a heated single-stage CSTR
scanning calorimetry (DSC) was used to assess the thermal was evaluated to immediately quench the N-chloramine.
stability of 11, which melts at 78 °C and decomposes between Flowing an aqueous solution of in situ generated 11 or 12 into a
Table 2: Batch vs flow study of reaction of N-chloramine with styrene.
entry
mode/substrate
catalyst (mol %)
temperature (°C)
time (min)
product
conversion (%)a
1
batch/9
batch/9
batch/9
batch/9
batch/9
batch/10
CSTR/9
2
2
2
0
0
2
0
100
80
15
15
60
60
60
60
14
14
14
14
14
15
14
62
98
50
100
0
2
3
rt
4
100
100
110
100
5b
6
100
7c
30
60
75
12
73
76
8c
CSTR/10
0
100
30
60
120
15
67
77
77
aConversion measured by 1H NMR spectroscopy. bReaction carried out in either air or presence of TEMPO (1 equiv) led to the same result. c1-Stage
CSTR, co-feed with styrene in toluene and substrate in toluene/diglyme 3:1.
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stream of toluene containing styrene (13) enabled the continu- produce any amide product. Likewise, attempts to couple
ous production of alkylated amine products 14 and 15 (Table 2, morpholine in place of its N-chloro derivative reached only
entries 7 and 8, respectively). In each case the tres was compa- 19% conversion.
rable with batch (reaction of 11 = 75 minutes, 12 = 60 minutes),
with steady-state conversions or 76 and 77% observed, respec- Following the investigation of the batch reaction, it was trans-
tively.
ferred to a CSTR. Feeding 200 mM N-chloramine to meet a
separate solution of aldehyde 17 (5 equiv) and t-BuO2H
(5 equiv), a tres of 100 minutes afforded amide 18 in
Reaction of N-chloramine with aldehyde
Reaction of N-chloramines with aromatic and aliphatic alde- 70% conversion at steady state. Under analogous conditions,
hydes to form amides has been reported by Porcheddu [34]. FeCl3 (5 mol %) was included in the oxidant stream to give
Under these literature conditions, FeCl3 catalyst (0.15 mol %), 96% steady-state conversion to 18 (Figure 3). This data repre-
t-BuO2H oxidant (3.6 equiv) and excess aldehyde 17 (5 equiv) sents productivities of 19 and 26 g L−1 h−1 for the uncatalysed
were employed to react with dilute N-chloramine 16 (0.064 M and FeCl3-catalyzed amide formation, respectively (Supporting
in MeCN), delivering amide 18 in 77% conversion and Information File 1, S4).
54% isolated yield. Our interests were to improve the produc-
tivity of this system, by exploiting higher concentrations of
N-chloramine produced in flow mode (200 mM). Table 3
summarizes a comparative study between batch and continuous
flow for this reaction.
Initial tests involving 200 mM substrate concentration afforded
amide 18 in 60% conversion (Table 3, entry 2). Increasing the
catalyst loading to 15 mol % led to a quantitative conversion of
18 within 1 hour reaction time. Unexpectedly, a control reac-
tion omitting the FeCl3 catalyst resulted in 90% conversion
following a two-hour reaction time (Table 3, entry 4).
Removing the t-BuO2H oxidant reduced the reaction rate signif-
icantly, leading to 10% conversion under otherwise identical
conditions (Table 3, entry 5), whilst fewer equivalents of alde-
Figure 3: Continuous-flow amide 18 formation using 1-stage CSTR.
Blue squares: FeCl3 included; red circles: FeCl3 not included.
hyde 17 led to 30% product formation (Table 3, entry 6).
Notably, other oxidants such as H2O2 and NaOCl failed to
Table 3: Batch vs flow study of reaction of N-chloramine with an aldehyde.
entry
mode
FeCl3 (mol %)
equiv 17/t-BuO2H
time (min)
conversion/yield (%)a
1b
2c
3
batch
batch
batch
batch
batch
batch
CSTR
CSTR
0.15
0.15
15
0
5/3.6
5/3.6
5/3.6
5/3.6
5/0
300
300
60
77/54
60
100
90
4
120
120
120
100
100
5
15
0
10
6
1/3.6
5/5
30
7
0
70d
96d
8
5
5/5
aConversion measured by gas chromatography as the average of three runs. bLiterature conditions quoted as 88% [34]. c[16] = 200 mM.
dConversion recorded at steady state.
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Beilstein J. Org. Chem. 2018, 14, 2220–2228.
Reaction of N-chloramine with base
alternative method of amine oxidation. A 5-stage cascade CSTR
The base-induced dehydrochlorination of N-chloramines is a was employed to link N-chloramine generation with base-
facile route to imines, which may be used for further functional- promoted imine formation. A 1 M stream of N-chloramine 5 in
ization. Our study began by examining a host of bases to toluene was mixed in the first CSTR with separate flows of
convert N-chloramine 5 to benzylidene(methyl)amine (19) as a aqueous NaOH and TBAB (10 mol % relative to substrate) and
model reaction system (Table 4).
tres was adjusted by changing the number of subsequent CSTR
chambers (n) (Table 5, entry 1). It is noteworthy that attempts to
To achieve a complete conversion, NEt3 was required in large mix NaOH and TBAB solutions via a T-piece prior to the
excess (5 equiv) over 42 hours, which proved unsuitable for mixing chamber were not successful, as a precipitate forms
continuous flow (Table 4, entry 1). Whilst KOt-Bu and NaOMe from the mixture leading to reactor blockage. A quantitative
bases allowed rapid imine formation (Table 4, entries 2–6), conversion of 5 to imine 19 was realized using the NaOH/
though their low solubility in MeOH or toluene would require TBAB protocol with a tres of 2 hours with good productivity
slurry pumping in flow mode which is undesirable. In addition, (0.25 mol L−1 h−1, Table 5, entry 1). Under analogous condi-
the isolation procedure is not straightforward, requiring multiple tions, N-chloramine 7 was converted to imine 20 in
unit operations. To avoid this, a phase-transfer catalyst (TBAB) 88% conversion, which could be improved to 99% conversion
was used along with NaOH (Table 4, entries 7–9). This reagent, by extending tres to 3 hours (Table 5, entry 2). However, the
in a toluene/water mixture, promoted full conversion to imine same conditions proved only able to convert 19% of the
19 (Table 4, entry 8). The separation of the toluene phase provi- N-chloramine 8 at steady state with tres of 2 h (Table 5, entry 3).
ded the imine product, which may be deployed directly in To achieve a higher conversion an impractical tres would
further reactions.
be required if the same batch conditions were used.
In this regard, the use of heated CSTRs would be useful to
To validate the batch protocol N-chloramines 5 and 7 under- explore.
went smooth dehydrochlorination to produce imines 19 and 20
in 83 and 100% conversion after 1 hour (Table 5, entries 1 and The formation of both imines 20 and 21 are of interest as an
2). The cyclic N-chloramine 8 was converted in batch mode to asymmetric reduction would give an optically pure amine. To
the corresponding imine 21, though required 18 hours to reach demonstrate this, imine 20, formed in situ, underwent asym-
84% conversion (Table 5, entry 3). The rapid nature of the metric-transfer hydrogenation in both batch and flow modes,
imine formation prompted us to investigate a fully continuous using [IrCp*Cl2]2 as catalyst with the ligand (R,R)-TsDPEN,
protocol to both N-chlorinate and subsequently dehydrochlori- using the hydrogen-donor reagent formic acid/triethylamine
nate amines, which would represent a mild and atom-efficient (Scheme 1).
Table 4: Batch optimization study of the dehydrochlorination of N-chloramines.
entry
base
catalyst
solvent
time (h)
conversion (%)a
1
NEt3 (5 equiv)
none
toluene
42
15
2
92
90
100
100
47
100
83
100
50
0
2
KOt-Bu (5 equiv)
NaOMe (2 equiv)
NaOMe (10 equiv)
NaOMe (1 equiv)
NaOMe (5 equiv)
NaOH 25% aq
NaOH 25% aq
NaOH 40% aq
NaOH 25% aq
NaOH 25% aq
none
MeOH
3
none
toluene/MeOH 1:1
toluene/MeOH 1:1
toluene/MeOH 1:1
toluene
4
none
1
5
none
1
6
none
1
7
TBABb
TBABb
TBABb
none
toluene/water 1:1
toluene/water 1:1
toluene/water 1:1
toluene/MeOH (1%)
toluene/MeOH (20%)
1
8
3
9
1
10
11
19
19
none
0
aMeasured by 1H NMR spectroscopy. bReaction temperature = 60 °C.
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Table 5: Batch vs flow study of the dehydrochlorination step.
entry
1
product
mode
tres (h)
conversion (%)a
batch
flow
1
2
83
100
19
batch
flow
flow
1
2
3
100
88
99
2
3
20
batch
flow
18
2
84
19
21
aMeasured by 1H NMR spectroscopy.
Scheme 1: Continuous-flow transfer hydrogenation of in situ generated imines.
Under batch conditions, a tres of 120 minutes gave quantitative Conclusion
reduction of the imine, affording the R-isomer in 86% ee. A continuous-flow approach to prepare and handle unstable
Translating the procedure to continuous flow, a fresh solution of N-chloramines is reported. The method exploits the superior
imine 20 and catalyst mixture were pumped into a heated CSTR mixing of a CSTR compared with classical batch, to enable fast
over a 30-minutes tres, affording chiral amine 22 in 94% ee with N-chlorination of amines under biphasic conditions. By virtue
complete conversion. It is unclear why a higher optical activity of a flowing solution, the in situ generated chloramines may be
was seen using continuous flow. However, it is known that transferred directly into new reaction media, with examples of
[IrCp*Cl2]2 can slowly racemise this amine which may be more (i) addition to an alkene to form a new C–N and C–Cl bond,
of a problem in batch with the longer reaction time [48].
(ii) reaction with aldehyde to produce amides, and (iii) dehy-
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Beilstein J. Org. Chem. 2018, 14, 2220–2228.
12.Worley, S. D.; Wojtowicz, J. A. Kirk-Othmer Encyclopedia of Chemical
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Acknowledgements
The research for this work has received funding from the Inno-
vative Medicines Initiative joint undertaking project Chem21
under grant agreement n°115360, resources of which are
composed of financial contribution from the European Union’s
Seventh Framework Programme (FP7/2007-2013) and EFPIA
companies in kind contribution.
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